rs6436669

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000091.5(COL4A3):c.485A>G(p.Glu162Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,609,424 control chromosomes in the GnomAD database, including 560,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 46870 hom., cov: 30)

Exomes 𝑓: 0.84 ( 513510 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.228

Variant links:

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jun 2010]

COL4A3 links:

MFF-DT (HGNC:41067): (MFF divergent transcript)

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2934814E-6).

BP6

Variant 2-227248459-A-G is Benign according to our data. Variant chr2-227248459-A-G is described in ClinVar as [Benign]. Clinvar id is 255001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227248459-A-G is described in Lovd as [Benign]. Variant chr2-227248459-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5 link	c.485A>G	p.Glu162Gly	missense_variant	Exon 9 of 52	ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 link	c.485A>G	p.Glu162Gly	missense_variant	Exon 9 of 52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.780

AC:

118480

AN:

151958

Hom.:

46841

Cov.:

show subpopulations

Gnomad AFR

AF:

0.626

Gnomad AMI

AF:

0.790

Gnomad AMR

AF:

0.847

Gnomad ASJ

AF:

0.778

Gnomad EAS

AF:

0.907

Gnomad SAS

AF:

0.860

Gnomad FIN

AF:

0.819

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.837

Gnomad OTH

AF:

0.776

GnomAD3 exomes

AF:

0.835

AC:

208114

AN:

249350

Hom.:

87492

AF XY:

0.837

AC XY:

113200

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.628

Gnomad AMR exome

AF:

0.887

Gnomad ASJ exome

AF:

0.775

Gnomad EAS exome

AF:

0.919

Gnomad SAS exome

AF:

0.857

Gnomad FIN exome

AF:

0.825

Gnomad NFE exome

AF:

0.835

Gnomad OTH exome

AF:

0.822

GnomAD4 exome

AF:

0.838

AC:

1221628

AN:

1457348

Hom.:

513510

Cov.:

AF XY:

0.838

AC XY:

607873

AN XY:

725274

show subpopulations

Gnomad4 AFR exome

AF:

0.622

Gnomad4 AMR exome

AF:

0.881

Gnomad4 ASJ exome

AF:

0.775

Gnomad4 EAS exome

AF:

0.890

Gnomad4 SAS exome

AF:

0.857

Gnomad4 FIN exome

AF:

0.826

Gnomad4 NFE exome

AF:

0.843

Gnomad4 OTH exome

AF:

0.826

GnomAD4 genome

AF:

0.780

AC:

118560

AN:

152076

Hom.:

46870

Cov.:

AF XY:

0.781

AC XY:

58037

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.626

Gnomad4 AMR

AF:

0.847

Gnomad4 ASJ

AF:

0.778

Gnomad4 EAS

AF:

0.907

Gnomad4 SAS

AF:

0.861

Gnomad4 FIN

AF:

0.819

Gnomad4 NFE

AF:

0.837

Gnomad4 OTH

AF:

0.775

Alfa

AF:

0.826

Hom.:

128506

Bravo

AF:

0.775

TwinsUK

AF:

0.829

AC:

3075

ALSPAC

AF:

0.846

AC:

3260

ESP6500AA

AF:

0.640

AC:

2326

ESP6500EA

AF:

0.828

AC:

6760

ExAC

AF:

0.830

AC:

100265

Asia WGS

AF:

0.848

AC:

2948

AN:

3478

EpiCase

AF:

0.823

EpiControl

AF:

0.829

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 92. Only high quality variants are reported. -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu162Gly in exon 9 of COL4A3: This variant is not expected to have clinical s ignificance because it has been identified in 91.38% (7859/8600) of East Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs6436669). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive Alport syndrome

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant Alport syndrome

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.54

DEOGEN2

Benign

0.063

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.10

MetaRNN

Benign

0.0000013

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.28

PROVEAN

Benign

1.3

REVEL

Benign

0.16

Sift

Benign

0.83

Sift4G

Benign

0.42

Polyphen

0.019

Vest4

0.065

MPC

0.23

ClinPred

0.0032

GERP RS

1.2

Varity_R

0.033

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over